In this project, we have found that immune T cells that are expanded ex vivo in the presence of rapamycin can develop resistance to rapamycin provided that necessary co-stimulation and cytokine signals are provided. Importantly, we have shown that a great variety of functional T cell subsets can be generated in rapamycin, including the Th1, Th2, Tc1, Tc2, and regulatory T cell subsets. Of significance, we have found that T cells that acquire rapamycin-resistance also attain an apoptosis resistance phenotype;this biology has functional significance because upon adoptive T cell transfer, such rapamycin- and apoptosis-resistant T cell have increased in vivo survival and therefore mediate more potent immune T cell reactions relative to control T cells. We have observed that this biology occurs with both murine T cells and human T cells. Given this understanding, we have initiated pilot clinical trials at the NIH Clinical Center using rapamycin-resistant T cells for the therapy of leukemia, lymphoma, and renal cell carcinoma.